Pharmaceutical compositions of sertaconazole for vaginal use

ABSTRACT

The invention relates to monodose mucoadhesive vaginal compositions of sertaconazole or a pharmaceutically acceptable salt thereof for the treatment of vulvovaginal candidiasis.

FIELD OF THE INVENTION

The present invention relates to compositions of sertaconazole forvaginal use and more specifically to compositions of sertaconazole forvaginal use in the treatment of vulvovaginal candidiasis.

BACKGROUND OF THE INVENTION

Vulvovaginal candidiasis is an inflammatory process that affects thevulva, the vagina or both together, and is caused by a superficialinfection of the epithelial cells, especially by the yeast Candidaalbicans and to a lesser extent by other Candida spp., such as C.glabrata, C. tropicalis, C. parapsilosis, C. guillermondi and C. krusei.Vulvovaginal candidiasis is characterised by vulvar pruritus, vaginalsecretion with or without true vaginitis, leucorrhoea, vulvar erythema,and maceration. As the prevalence of this disease is increasing, theresearch for and development of new antifungal preparations is fullyjustified. It is nowadays accepted that oral and intravaginal antifungaldrugs are similarly effective in the treatment of uncomplicatedvulvovaginal candidiasis. Since it is usually preferable to administermedicines topically rather than orally, especially in pregnant women,local treatment of vulvovaginal candidiasis is consequently recommendedand oral drug delivery should be avoided whenever possible.

U.S. Pat. No. 4,551,148 describes systems for vaginal deliveryconsisting of emulsions or suspensions of nystatin with characteristicsof bioadherence to the vaginal surface. On the other hand, U.S. Pat. No.5,266,329 describes systems for vaginal delivery consisting of emulsionsor suspensions of imidazole antifungal agents with characteristics ofbioadherence to the vaginal surface.

WO95/31178 describes emulsions and aqueous solutions of itraconazolewith cyclodextrin for vaginal use.

U.S. Pat. No. 5,514,698 describes long-lasting antifungal vaginal creamsthat have a stable viscosity in the human body.

EP 770384 describes anhydrous solid pharmaceutical compositions ofantimycotic agents, antiprotozoal agents, disinfectants, hormones,antibiotics and chemotherapeutic agents for vaginal use containingpolycarbophil as a unique mucoadhesive polymer. Similarly, EP 918510describes gels of polycarbophil-azole complexes with antifungal, orantiprotozoal activity, in which the polycarbophil acts as amucoadhesive polymer.

WO00/30626 describes a method for treating vulvovaginal candidiasisconsisting of the intravaginal administration of a single dose of anovule of miconazole nitrate as well as the application of miconazolenitrate cream to the vulva.

WO02/03896 describes a method for treating vaginal or uterine infectionscaused by fungi, bacteria, viruses or parasites that consists ofbringing the vaginal epithelium into contact with an intravaginal devicethat contains an antifungal agent, an antibacterial agent, an antiviralagent or a trichomonocidal agent, including a lipophilic or hydrophilicexcipient, a mucoadhesive agent and a penetration enhancer of the activeingredient.

DE-A-19737348 describes synergistic combinations of clindamycin andclotrimazole in the form of tablets, pessaries and ovules for localtreatment of bacterial and fungal infections of the vagina.

WO 99/55333 describes synergistic combinations of at least two imidazoleingredients for locally combating the microorganisms that causevulvovaginitis and vaginosis.

WO 03/032948 describes compositions and methods for deliveringantibacterial, antifungal and antiviral ointments to the oral, nasal orvaginal cavity. Said compositions may contain one or more bioadhesiveagents, such as xanthan gum and sodium carboxymethylcellulose.

WO 99/13862 relates to pharmaceutical compositions comprising apharmaceutically acceptable bioadhesive carrier for vaginaladministration. The bioadhesive carrier is a cross-linked polycarboxylicacid polymer formulation. Suitable cross-linking agents include divinylglycol, divinylbenzene, N,N-dialkylacrylamide,3,4-hydroxy-1,5-hexadiene, 2,5-dimethyl-1,5-hexadiene and similaragents. Suitable polycarboxylic acids include polyacrylic andpolymethacrylic acids.

In Torres et al., International Journal of Gynecology & Obstetrics 71(2000) 53-520 the use of sertaconazole in gynecology is described. Theformulations and doses tested were 300 mg sustained release vaginalovule, 500-mg vaginal tablet (both single dose) and 2% vaginal cream inrepeated applications for 7 days.

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is to provide new compositions ofsertaconazole for vaginal use in the treatment of vulvovaginalcandidiasis. More specifically, the present invention relates tomucoadhesive vaginal compositions of sertaconazole in single-dose dosageforms for the treatment of vulvovaginal candidiasis.

No composition of sertaconazole with the aforesaid characteristics hasbeen described to date.

Sertaconazole is a broad-spectrum antifungal agent with excellentactivity against yeasts, dermatophytes, and opportunistic fungi. Inaddition to its antifungal efficacy, sertaconazole has a good safetyprofile, sustained cutaneous retention and low systemic absorption. Allthese properties make it be an ideal product for topical application.For reference, the in vitro activities, expressed as minimum inhibitoryconcentrations (MIC), of sertaconazole, bifonazole and econazole againstmostly prevalent Candida spp. in vulvovaginal candidiasis are shown inTable 1 (Carrillo-Muñoz A. J. and Torres-Rodriguez J. M., J. Antimicrob.Chemother. 1995: 36, 713-716). TABLE 1 Microorganism SertaconazoleBifonazole Econazole C. albicans (73) 1.02 3.6 2.24 C. tropicalis (21)1.67 9.51 3.14 C. glabrata (16) 0.78 4.09 2.39 C. parapsilosis (22) 0.313.76 0.75 C. krusei (13) 0.38 2.20 0.91 C. guillermondii (5) 0.51 3.871.11

Furthermore, sertaconzole is superior to most imidazole antifungal drugsas a fungicide against C. albicans (Palacín C., Sacristán A. and OrtizJ. A., Arzneim. Forschung, 1992: 42(I), 711-714; Agut J., Palacín C. andOrtiz J. A., Arzneim. Forschung 1992, 42(I), 721-724).

In contrast to prior-art compositions, the present invention ischaracterised by the presence of one or more mucoadhesive excipients.These mucoadhesive excipients are preferably selected from cellulosepolymers, such as carboxymethylcellulose, hydroxypropyl methylcellulose,methylcellulose and the like, or from polyacrylic acid-derivativepolymers, such as carbomers, polycarbophils and the like. The applicantshave discovered that, surprisingly, the combination of a polycarbophiland a carbomer enhances the mucoadhesive action of the preparation, butnot the absorption of sertaconazole. Consequently, the activeingredient, sertaconazole, remains in the mucosa of the vagina for aperiod of 3 to 5 days, its absorption (permeation) through the vaginalmucosa being less than 0.1% of the dose. As a result, systemic sideeffects are negligible. The resulting intravaginal preparation requiresjust a single-dose application to achieve a convenient and safeeradication of Candida spp., which is very advantageous in practice.

The excipients used in the present invention are classified aslipophilic, mucoadhesive and preservative. Among the possibleexcipients, which are not intended to restrict the scope of the presentinvention, the following are preferred:

-   -   a) Lipophilic excipients: Glyceryl stearates and derivatives,        for example, polyethylene glycol stearates, ketostearyl        alcohols, polyoxyethylene glycol ethers of n-alcohols (lauryl,        cetyl, stearyl and myristyl alcohol), liquid paraffin, lecithin        oil, glycerol and the like. The applicants have discovered that        the combination of palmitate stearate of ethyleneglycol and        polyethylene glycol (Tefose 63), saturated polyglycolised        glycerides (Labrafil M2130CS), glyceryl isostearate (isostearic        peceol) and liquid paraffin proves very suitable for the        implementation of the present invention. As a whole, the        lipophilic excipients are present in a total proportion of from        10 to 40%, preferably from 30 to 35%, of the composition.    -   b) Mucoadhesive excipients: Cellulose polymers selected from        sodium carboxymethylcellulose, hydroxypropyl methylcellulose,        methylcellulose and the like, gelatin, colloidal anhydrous        silica, or polyacrylic acid polymers, such as carbomers and        polycarbophils. All these mucoadhesive excipients also possess        gel-forming capacity. The applicants have discovered that the        combination of polyacrylic acid cross-linked with divinyl glycol        (e.g. polycarbophil AA-1) and acrylic acid cross-linked with        allyl esters of sucrose or pentaerythritol (e.g. carbopol 974P        or carbopol 934P) proves very suitable for the implementation of        the present invention. As a whole, the mucoadhesive excipients        with gel-forming properties are present in a total proportion        between 0.1 and 3%, preferably between 1 and 1.5% of the        composition.    -   c) Preservatives: Parabens, such as methylparaben, butylparaben        or propylparaben, benzoic acid, sorbic acid, boric acid and the        like. As a whole, the preservatives are present in a total        proportion between 0.01 and 0.3%, preferably between 0.1 and        0.2% of the composition.

Optionally, the compositions of the present invention can contain inaddition suspending agents and humectants, such as povidone or propyleneglycol, and neutralising agents for adjusting the viscosity of thecomposition, such as sodium hydroxide, triethanolamine (TEA) orethylenediamine tetraacetic acid (EDTA). Povidone is normally used inconcentrations of from 1 to 3% of the composition, preferably 2%. As forpropylene glycol, it is normally used from 5 to 10% of the composition,preferably 7%.

Among the possible compositions, the invention relates preferably tocreams and gels. For preparation of the compositions of the presentinvention, sertaconazole can be used as free base or in the form of apharmaceutically acceptable salt. Among the pharmaceutically acceptablesalts, the nitrate is preferred. The compositions may also containmixtures of the free base with one or more salts as well as mixtures oftwo or more salts.

The cream formulations can be applied at two different concentrations ofsertaconazole. The highest concentration cream is applied inside thevagina and the lowest concentration is applied on the periphery of theinfected zone, the vulva. The present invention relates more preciselyto the cream for internal application, administered in a single dose.The concentration of sertaconazole nitrate in this cream composition canrange from 2 to 10%, and its quantity by volume can range from 4 to 6ml. This corresponds to a dose of from 80 to 600 mg sertaconazolenitrate. According to one embodiment, the concentration is higher than2%, 3%, 4%, 5% or 6% and, in particular, ranges from 3 to 10%, or 4 to9%. A concentration of from 5 to 8%, and more preferably from 6 to 7% ispreferred. A volume of 5 ml is preferred. This corresponds to a dose offrom 250 to 400 mg and more preferably from 300 to 350 mg sertaconazolenitrate. For sertaconazole and sertaconazole salts other than thenitrate the same concentrations apply. Alternatively, the presentinvention also relates to gels for application inside the vagina, whichcan be administered in a single dose. The concentration of the activeingredient in the gel formulations is similar to that of thecorresponding cream formulations. However, the gels in contrast to thecreams, do not necessarily contain lipophilic excipients in theirformulation. For proper administration of these formulations (creams andgels), they can be conveniently packed inside an applicator, such asthat described in ES 2,133,090, which constitutes one of the objects ofthe present invention. The size of the crystals of sertaconazole nitratein the resulting cream should be below 80 μm. Preferably, micronizedsertaconazole nitrate having a particle size below 80 μm is used.

On the other hand, the conventional cream for vulvar applicationmentioned in the preceding paragraph has a concentration ofsertaconazole nitrate between 1 and 3%, preferably 2%. Its volume canrange from 5 to 15 ml, preferably 10 ml. In the case of the cream or gelformulations for internal application, single or repeated doses can beadministered. This cream composition is used for alleviating itching andirritation outside the vagina (in the vulva) in women infected withCandida spp. in both the vulva and the vagina, and represents asupplemental vaginal therapy with the concentrated cream or gelformulations, as described in the preceding paragraph.

Thus, a preferred embodiment of the present invention is a kit with thetwo formulations. The concentrated cream or gel formulation for internaluse is conveniently packed in an applicator and prepared for itsapplication in a single dose. The conventional cream for external use ispacked in a conventional tube for its application in a single orrepeated dose.

The release of sertaconazole nitrate from the two formulations, aconcentrated intravaginal cream formulation (Example 1) and aconventional cream formulation, was tested. The formulation of thepresent invention releases the active ingredient in a slow releaseprofile, in contrast to the conventional cream formulation, which isalso used for the treatment of the external area (vulva).

Unless indicated otherwise, concentrations and proportions given aspercentage [%] refer to weight and thus mean “% by weight”.

The present invention is further illustrated by—but not limited to—thefollowing examples.

EXAMPLE 1 Preparation of 100 g of Cream for Intravaginal Administration

Composition Micronised sertaconazole nitrate particle size 6.00 g below80 μm Tefose 63¹ 20.00 g Labrafil M 2130 CS² 5.00 g Isostearic peceol³2.00 g Paraffin oil 8.00 g Benzoic acid 0.10 g Polycarbophil⁴ AA-1 1.00g Carbopol 974 P⁵ 0.30 g Purified water q.s. for 100.00 g¹Tefose 63: Ethylene glycol and polyethylene glycol palmitate stearate²Labrafil M 2130 CS: Saturated polyglycol glycerides³Isoestearic peceol: Glyceryl isostearate⁴Polycarbophil AA-1: Polyacrylic acid cross-linked with divinyl glycol⁵Carbopol 974 P: Carbomer. Acrylic acid polymer cross-linked withsucrose and pentaerythritol allyl esters.Physicochemical PropertiesAppearance: White, odourless (or slight oily odour), semisolid cream offluid consistency.Penetrability: 43.5±5% mm.Viscosity: 347,000 cps±45% (25° C.).

EXAMPLE 2 In Vitro Dissolution and Transdermal Permeation Tests

The in vitro dissolution and transdermal permeation tests ofsertaconazole nitrate from the cream formulations of Example 1 wereevaluated in comparison with a conventional cream formulation of 2%sertaconazole nitrate.

The composition for 100 g of the conventional cream is as follows:Micronised sertaconazole nitrate with particle size 2.00 g below 80 μmTefose 63¹ 20.00 g Labrafil MS 2230² 5.00 g Isostearic peceol³ 2.00 gParaffin oil 8.00 g Nipagin⁴ 0.10 g Sorbic acid 0.10 g Purified waterq.s. for 100.00 g¹Tefose 63: Ethylene glycol and polyethylene glycol palmitate stearate²Labrafil MS 2230: Saturated (C₁₀-C₁₈) polyoxyethylene glycol and glycolglycerides³Isoestearic peceol: Glyceryl isostearate⁴Nipagin: Methyl p-hydroxybenzoate.

Both tests were carried out with Franz cell-type diffusion systems, witha diffusional area of 2.54 cm². 1 ml of cream was placed in the donorcompartment and 11 ml of a suitable receptor medium were placed in thereceptor compartment. For the dissolution test, a 0.45-μm Milliporemembrane of nylon esters was used, and the receptor medium was made upof a mixture of ethanol-water (1:1). Vaginal epithelium was used aspermeation membrane and phosphate buffer solution at pH 7.4 was used asthe receptor medium.

The 4-cm² membranes used in the permeation test were formed byreconstituted vaginal epithelial cells (5-day culture) from transformedcells of human vaginal epithelium on polycarbonate support. These cellswere obtained from cell lines of vulvar epidermoid carcinomas. The testtemperature was 32° C. for both cases.

In the light of the physicochemical properties of sertaconazole, it canbe assumed that the maximum quantity permeated is about 1% of thequantity located on the membrane. Under such assumption, the maximumquantity of sertaconazole that reaches the receptor compartment is 6.18g/ml.

The curves showing the release of sertaconazole nitrate from the twocream formulations are plotted in FIG. 1. Starting from 5 ml of thecream formulation of Example 1, 125 mg of the active ingredient havealready been released at 24 hours and on the following days at the rateof 50-60 mg/day. Thus, it is observed that the delivery of the activeingredient is 81% after 5 days.

Moreover, the in vitro permeation test shows that the active substancepresent in the vaginal cream formulation of Example 1 permeates lessthan 0.1% of the dose.

The toxicity study performed to assess the non-clinical vaginaltolerance of the mucoadhesive cream proves a good tolerance after beingapplied at single or repeated doses to rats (method according toCMP/SWP/21H5/00).

EXAMPLE 3 Preparation of 100 g of Gel for Intravaginal Administration

Starting from the appropriate components and according to standardprocedures of pharmaceutical technology, the following gel compositionwas obtained: Micronised sertaconazole nitrate with particle size 6.00 gbelow 80 μm Carbopol 974 P¹ 0.70 g Polycarbophil AA-1² 0.30 g Propyleneglycol 7.00 g Nipagin³ 0.16 g Nipasol⁴ 0.04 g Povidone 2.00 g TEA⁵ *Purified water q.s. for 100.00 g¹Carbopol 974 P: Carbomer. Acrylic acid polymer cross-linked withsucrose and pentaerythritol allyl esters.²Polycarbophil AA-1: Polyacrylic acid cross-linked with divinyl glycol³Nipagin: Methyl p-hydroxybenzoate⁴Nipasol: Propyl p-hydroxybenzoate⁵TEA: Triethanolamine* Quantity sufficient to adjust the viscosity

1. A vaginal mucoadhesive composition for single dose administration, which is a cream or a gel and comprises sertaconazole or one of its pharmaceutically acceptable salts wherein the proportion of sertaconazole or the salt is higher than 2% and does not exceed 10%.
 2. The composition of claim 1, wherein the proportion of sertaconazole or the salt is from 3 to 10%.
 3. The composition of claim 1 or 2, which is a cream.
 4. The composition of claim 1, wherein the pharmaceutically acceptable salt is sertaconazole nitrate.
 5. The composition of claim 4, wherein the proportion of sertaconazole nitrate is from 6 to 7%.
 6. The composition of claim 1, wherein the cream contains lipophilic excipients, mucoadhesive excipients and one or more preservatives, and the gel dosage form contains mucoadhesive excipients and one or more preservatives.
 7. The composition of claim 6, wherein the lipophilic excipients are selected from glyceryl stearates and their derivatives, ketostearyl alcohols, polyoxyethylene glycol ethers of n-alcohols, liquid paraffin, lecithin oil, glycerol and the like.
 8. The composition of claim 7, wherein the lipophilic excipients are present in a total proportion of from 10 to 40%.
 9. The composition of claim 8, wherein the lipophilic excipients are present in a total proportion of from 30 to 35%.
 10. The composition of claim 6, wherein the mucoadhesive excipients are selected from cellulose polymers, gelatin, colloidal anhydrous silica and polyacrylic acid polymers.
 11. The composition of claim 10, wherein the mucoadhesive excipients are polyacrylic acid polymers.
 12. The composition of claim 11, wherein the polyacrylic acid polymers form a mixture of polyacrylic acid polymer cross-linked with divinyl glycol and acrylic acid polymer cross-linked with sucrose or pentaerythritol allyl esters.
 13. The composition of claim 12, wherein the mixture of polyacrylic acid polymer cross-linked with divinyl glycol and acrylic acid polymer cross-linked with sucrose or pentaerythritol allyl esters are present in a proportion of from 0.1 to 3%.
 14. The composition of claim 13, wherein the mixture of polyacrylic acid polymer cross-linked with divinyl glycol and acrylic acid polymer cross-linked with sucrose or pentaerythritol allyl esters are present in a proportion of from 1 to 1.5%.
 15. The composition of claim 6, wherein the preservatives are selected from parabens, benzoic acid, sorbic acid, boric acid and the like.
 16. The composition of claim 15, wherein the preservatives are present in a total proportion of from 0.01 to 0.3%.
 17. The composition of claim 16, wherein the preservatives are present in a total proportion of from 0.1 to 0.2%.
 18. The composition of claim 1, wherein its content is packed in a single-dose applicator.
 19. The composition of claim 18, wherein its capacity is from 4 to 6 ml.
 20. The composition of claim 19, wherein its capacity is 5 ml.
 21. A kit comprising the composition according to claim 1, and a cream composition for vulvar application containing sertaconazole or one of its pharmaceutically acceptable salts.
 22. The kit of claim 21, wherein the pharmaceutically acceptable salt is sertaconazole nitrate.
 23. The kit of claim 22, wherein sertaconazole nitrate is present in a proportion of from 1 to 3%.
 24. The kit of claim 23, wherein sertaconazole nitrate is present in the proportion of 2%.
 25. Use of the composition according to claim 1 for the manufacture of a pharmaceutically acceptable dosage form for the treatment of vulvovaginal candidiasis of the vagina.
 26. A method for treating vulvovaginal candidiasis, wherein the composition of claim 1 is administered into the vagina of a subject in need of such treatment in a single dose.
 27. The method of claim 26, wherein additionally a composition containing sertaconazole or one of its pharmaceutically acceptable salts is applied to the vulva in single or repeated dose. 